Dose-Dependent Cellular and Systemic Pharmacokinetics of Cytosine Arabinoside

  • R. L. Capizzi
  • J. C. White
Conference paper
Part of the Haematology and Blood Transfusion / Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 34)


The proper selection of dose for any desired therapeutic effect must consider the drug’s systemic and cellular pharmacokinetics. Pharmacokinetics, the measurement of drug concentration over time, is essential to the attainment of a desired pharmacodynamic effect. Correlation of cellular pharmacokinetics with systemic pharmacokinetics offers opportunities for optimal dosage and schedule selection so as to achieve the optimal therapeutic index.


Acute Myeloid Leukemia Acute Myeloid Leukemia Cell Cytosine Arabinoside Leukemic Blast Nucleoside Transport 
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  1. 1.
    Gale RP (1979) Advances in the treatment of acute myelogenous leukemia. N Engl J Med 300: 1189–1199PubMedCrossRefGoogle Scholar
  2. 2.
    Capizzi RL, Powell BL (1987) Sequential high dose ara-C and asparaginase versus high dose ara-C alone in the treatment of patients with relapsed and refractory acute leukemias. Semin Oncol 14: 40–50PubMedGoogle Scholar
  3. 3.
    Preisler HD, Davis RB, Kirshner J, Dupre E, Richards E, Hoagland HC, Kopel S, Levy RN Carey R, Schulman P et al. (1987) Comparison of three remission induction regimens and two postinduction strategies for the treatment of acute nonlymphocytic leukemia: a Cancer and Leukemia Group B study. Blood 69: 1441–1449PubMedGoogle Scholar
  4. 4.
    Plagemann PGW, Marz R, Wohlhueter RM (1978) Transport and metabolism of deoxy-cytidine and l-3-D-arabinofuranosylcyto-sine into cultured Novikoff rat hepatoma cells, relationship to phosphorylation, and regulation of triphosphate synthesis. Cancer Res 38: 978–989PubMedGoogle Scholar
  5. 5.
    Kufe D, Major P, Egan E, Beardsley P (1981) Incorporation of ara-C into L1210 DNA as a correlate of cytotoxicity. J Biol Chem 235: 3235–3239Google Scholar
  6. 6.
    Kufe D, Spriggs D, Egan EM, Munroe D (1984) Relationships among ara-CTP pools, formation of (ara-C)DNA, and cytotoxicity of human leukemic cells. Blood 64: 54–58PubMedGoogle Scholar
  7. 7.
    Major PP, Egan EM, Beardsley GP, Minden MD, Kufe D (1981) Lethality of human myeloblasts correlates with the incorporation of arabinofuranosylcytosine into DNA. Proc Natl Acad Sci USA 78: 3235–3239PubMedCrossRefGoogle Scholar
  8. 8.
    White JC, Rathmell JP, Capizzi RL (1987) Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemia cells. J Clin Invest 79: 380–387PubMedCrossRefGoogle Scholar
  9. 9.
    Cass CE, Gaudette LA, Paterson ARP (1974) Mediated transport of nucleosides in human erythrocytes. Specific binding of the inhibitor nitrobenzythioinosine to nucleoside transport sites in the erythrocyte membrane. Biochim Biophys Acta 345: 1–10PubMedCrossRefGoogle Scholar
  10. 10.
    White JC, Hines LH, Rathmell JP (1985) Inhibition of l-3-D-arabinofuranosylcyto-sine transport and net accumulation by teni-poside and etoposide in Ehrlich ascites cells and human leukemic blasts. Cancer Res 45: 3070–3075PubMedGoogle Scholar
  11. 11.
    White JC, Capizzi RL (1991) A critical role for uridine nucleotides in the regulation of deoxycytidine kinase and the concentration dependence of l-3-D-arabinofuranosylcyto-sine phosphorylation in human leukemia cells. Cancer Res (in press)Google Scholar
  12. 12.
    Wiley JS, Jones SP, Sawyer WH, Paterson ARP (1982) Cytosine arabinoside influx and nucleoside transport sites in acute leukemia. J Clin Invest 69: 479–89PubMedCrossRefGoogle Scholar
  13. 13.
    Wohlhueter RM, Plagemann PGW (1980) The roles of transport and phosphorylation in nutrient uptake in cultured animal cells. Int Rev Cytol 64: 171–240PubMedCrossRefGoogle Scholar
  14. 14.
    Capizzi RL, Oliver L, Friedman H, Davis R, Mayer R, Schiffer C, Lunghofer B, Royer G (1988) Variations in ara-C plasma concentrations at steady-state (Cpss) during remission induction and intensification therapy of AML. A population pharmacokinetics study by CALGB. Proc Am Soc Clin Oncol 7: 57 (abstract)Google Scholar
  15. 15.
    Camiener GW (1968) Studies of the enzymatic deamination of ara-cytidine-V. Inhibition in vitro and in vivo by tetrahydrouridine and other reduced pyrimidine nucleosides. Biochem Pharmacol 17: 1981–1991PubMedCrossRefGoogle Scholar
  16. 16.
    Ho DHW, Frei E (1971) Clinical pharmacology of l-3-D-arabinofuranosylcytosine. Clin Pharmacol Ther 12: 944–954PubMedGoogle Scholar
  17. 17.
    Harris AL, Potter C, Bunch C (1979) Pharmacokinetics of cytosine arabinoside in patients with myeloid leukemia. Br J Clin Pharmacol 8: 219–227PubMedGoogle Scholar
  18. 18.
    Slevin ML, Piall EM, Aherne GW, Johnston A, Sweatman MC, Lister TA (1981) The pharmacokinetics of subcutaneous cytosine arabinoside in patients with acute myelogenous leukemia. Br J Clin Pharmacol 12: 507–510PubMedGoogle Scholar
  19. 19.
    Van Prooijen R, Van Der Kleijn E, Haanen C (1977) Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia. Clin Pharmacol Ther 21: 744–752PubMedGoogle Scholar
  20. 20.
    Wan SH, Hoffman DH, Azarnoff DL (1974) Pharmacokinetics of l-3-D-arabinofurano-sylcytisone in humans. Cancer Res 34: 392–397PubMedGoogle Scholar
  21. 21.
    Capizzi RL, Yang J-L, Cheng E, Bjornson D, Sahasrabudhe D, Tan R-S, Cheng Y-C (1983) Alteration of the pharmacokinetics of high dose araC by its metabolite, high araU in patients with acute leukemia. J Clin Oncol 1: 763–771PubMedGoogle Scholar
  22. 22.
    Powis G (1983) Metabolism, therapeutic effect, on toxicity of anticancer drugs in man. Drug Metab Rev 14: 1145–1163PubMedCrossRefGoogle Scholar
  23. 23.
    Darnowski JW, Handschumacher RE (1986) Tissue uridine pools: evidence in vivo of a concentrative mechanism for uridine uptake. Cancer Res 46: 3490–3494PubMedGoogle Scholar
  24. 24.
    Muller WEG, Zahn RK (1979) Metabolism of 1-p-D-arabinofuranosyluracil in mouse L5178Y cells. Cancer Res 39: 1102–1107PubMedGoogle Scholar
  25. 25.
    Liliemark JO, Plunkett W (1986) Regulation of l-3-D-arabinofuranosylcytosine 5’-tri-phosphate accumulation in human leukemia cells by deoxycytidine 5’-triphosphate. Cancer Res 46: 1079–1083PubMedGoogle Scholar
  26. 26.
    Chiba P, Tihan T, Eher R, Koller U, Wallner C, Gobi R, Linkesch W (1989) Effect of cell growth and cell differentiation on 1–3-D- arabinofuranosylcytosine metabolism in myeloid cells. Br J Haematol 71: 451–455PubMedCrossRefGoogle Scholar
  27. 27.
    Arner ES, Flygar M, Bohman C, Wallstrom B, Eriksson S (1988) Deoxycytidine kinase is constitutively expressed in human lymphocytes: consequences for compartmentation effects, unscheduled DNA synthesis, and viral replication in resting cells. Exp Cell Res 178: 335–342PubMedCrossRefGoogle Scholar
  28. 28.
    Richel DJ, Colly LP, Arentsen-Honders MW, Starrenburg CWJ, Willemze R (1990) Deoxycytidine kinase, thymidine kinase and cyti-dine deaminase and the formation of Ara- CTP in leukemic cells in different phases of the cell cycle. Leuk Res 14: 363–369PubMedCrossRefGoogle Scholar
  29. 29.
    Yang J-L, Cheng EH, Capizzi RL, Cheng Y-C, KuteT (1985) Effect of uracil arabino-side on metabolism and cytotoxycity of cyto-sine arabinoside in L5178Y murine leukemia. J Clin Invest 75: 141–146PubMedCrossRefGoogle Scholar
  30. 30.
    Chandrasekaran B, Capizzi RL, Kute TE, Morgan T, Dimling J (1989) Modulation of the metabolism and pharmacokinetics of l-3-D-arabinofuranosylcytosine by 1–3-D- arabinofuranosyluracil in leukemic mice. Cancer Res 49: 3259–3266PubMedGoogle Scholar
  31. 31.
    Weinstein HJ, Griffin TW, Feeney J, Cohen HJ, Propper RD, Sallan SE (1982) Pharmacokinetics of continuous intravenous and subcutaneous infusions of cytosine arabinoside. Blood 59: 1351–1353PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • R. L. Capizzi
    • 1
  • J. C. White
    • 1
  1. 1.Bowman Gray School of MedicineComprehensive Cancer Center of Wake Forest UniversityWinston-SalemUSA

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